Conserved regions on the HIV-1 envelope spike are important for vaccine design due to their vulnerability to antibodies that can block virus infectivity – termed neutralizing antibodies (NAbs). The CD4-binding site (CD4bs) on the HIV spike subunit gp120 is one such region. Eliciting antibody responses to the CD4bs is difficult because it is surrounded by sequence-variable segments. Here, I conducted immunizations in mice to investigate approaches to focus NAb responses to the CD4bs. I found that formulating gp120 mutants that preferentially expose the CD4bs with the saponin adjuvant QuilA improved CD4bs-directed responses; however neutralizing activity was not enhanced. In subsequent work I found that priming animals with a gp120 mutant fused to a string of pathogen-derived CD4 T-helper epitopes followed by booster injections with alternate gp120 constructs that differentially present the CD4bs elicited higher antibody titers and improved neutralizing activity. Overall, my work provides insight into strategies for focusing antibody responses to desired epitope targets with relevance to HIV vaccine design.
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Thesis advisor: Pantophlet, Ralph
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